SNA-modified antisense oligonucleotides: A new pathway for renal targeting?

Antisense oligonucleotides (ASOs) have emerged as a powerful class of therapeutics capable of suppressing gene expression with remarkable specificity. However, the clinical applications of ASOs have been limited by delivery challenges and toxicities, particularly when repeated or high dosing is required. In the study by Tsuboi et al., the authors present serinol nucleic acid (SNA)-modified gapmer ASOs that target the sodium-glucose cotransporter 2 (SGLT2) in mouse kidneys. With promising results, these SNA-modified ASOs display dose-dependent efficacy, prolonged knockdown, and importantly, a more favorable safety profile in both the kidney and liver compared with the 2'-MOE-modified counterpart. While some caveats remain-particularly around high-dose toxicity-these findings open the door to an approach that couples potency with improved tolerability, thereby highlighting SNA-modified ASOs as a potential next-generation platform for renal diseases.